US20040110954A1 - Methods of synthesizing phenol-contining compounds - Google Patents

Methods of synthesizing phenol-contining compounds Download PDF

Info

Publication number
US20040110954A1
US20040110954A1 US10/473,105 US47310503A US2004110954A1 US 20040110954 A1 US20040110954 A1 US 20040110954A1 US 47310503 A US47310503 A US 47310503A US 2004110954 A1 US2004110954 A1 US 2004110954A1
Authority
US
United States
Prior art keywords
alkyl
heteroaryl
aryl
hydroxy
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/473,105
Other languages
English (en)
Inventor
Michael Palovich
Katherine Widdowson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Priority to US10/473,105 priority Critical patent/US20040110954A1/en
Assigned to SMITHKLINE BEECHAM CORPORATION reassignment SMITHKLINE BEECHAM CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WIDDOWSON, KATHERINE L., PALOVICH, MICHAEL R.
Publication of US20040110954A1 publication Critical patent/US20040110954A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/43—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • This invention relates to the method of placing a sulfone or sulfonamide group ortho to a phenol in a drug substance in order to increase the metabolic stability and the half-life of the compound, while maintaining the acidity of the phenol.
  • Phenols are often found to be important pharmacophores for a number of target receptors, such as interleukin-8, opioid, dopamine, seritonin, COX1, COX2, andrenergic, and estrogen receptors. They are also found in a number of enzyme inhibitors such as betalactamases and topoisomerases.
  • target receptors such as interleukin-8, opioid, dopamine, seritonin, COX1, COX2, andrenergic, and estrogen receptors.
  • enzyme inhibitors such as betalactamases and topoisomerases.
  • drugs containing phenols is often limited by the short half-lives of these compounds due to conjugative metabolism via glucuronidation and/or sulfation of the phenol (see Mulder, G. J. and Meerman, J. H. Conjugative Reactions in drug Transformation edited by A.
  • morphine which contains a phenol, has a short half-life and high first pass clearance which limits it to intravenous administration.
  • the major metabolite of phenol containing drugs such as morphine, acetaminophen and albuterol is glucuronidation or sulfation of the phenol (PDR).
  • This invention relates to the method of placing a sulfone or sulfonamide group ortho to a phenol in a drug substance in order to increase the metabolic stability and the half-life of the compound, while maintaining the acidity of the phenol.
  • R b is independently selected from the group consisting of hydrogen, NR 6 R 7 , OH, OR a , C 1-5 alkyl, aryl, aryl C 1-4 alkyl, aryl C 2-4 alkenyl, cycloalkyl, cycloalkyl C 1-5 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heteroaryl C 2-4 alkenyl, heterocyclic, heterocyclic C 1-4 alkyl, and a heterocyclic C 2-4 alkenyl moiety, all of which moieties may be optionally substituted one to three times independently by a substituent selected from the group consisting of halogen, nitro, halosubstituted C 1-4 alkyl, C 1-4 alkyl, amino, mono or di-C 1-4 alkyl substituted amine, OR a C(O)R a , NR a C(O)OR a , OC(O)NR 6 R 7 , hydroxy,
  • R 1 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, C 1-10 alkyl, halosubstituted C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkoxy, halosubstituted C 1-10 alkoxy, azide, S(O) t R 4 , (CR 8 R 8 ) q S(O) t R 4 , hydroxy, hydroxy substituted C 1-4 alkyl, aryl, aryl C 1-4 alkyl, aryl C 2-10 alkenyl, aryloxy, aryl C 1-4 alkyloxy, heteroaryl, heteroaryl alkyl, heteroaryl C 2-10 alkenyl, heteroaryl C 1-4 alkyloxy, heterocyclic, heterocyclic C 1-4 alkyl, heterocyclic C 1-4 allyloxy, heterocyclic C 2-10 alkenyl, NR 4 C(O)NR 4 R 5 , NR 4 C(S) NR
  • R 1 moieties together may form O—(CH 2 ) s O or a 5 to 6 membered saturated or unsaturated ring, wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moieties may be optionally substituted;
  • R 4 and R 5 are independently selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl, heterocyclic, and heterocyclic C 1-4 alkyl; or R 4 and R 5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from oxygen, nitrogen and sulfur;
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, C 1-4 alkyl, heteroaryl, aryl, aklylaryl, and alkyl C 1-4 heteroalkyl; or R 6 and R 7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom is selected from oxygen, nitrogen or sulfur, and which ring may be optionally substituted;
  • R a is selected from the group consisting of alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, COOR a , and a heterocyclic C 1-4 alkyl moiety, all of which moieties may be optionally substituted;
  • R 8 is hydrogen or C 1-4 alkyl
  • R 9 is hydrogen or a C 1-4 alkyl
  • R 10 is C 1-10 alkyl C(O) 2 R 8 ;
  • R 11 is selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl, optionally substituted heterocyclic, and optionally substituted heterocyclic C 1-4 alkyl;
  • R 13 is selected from the group consisting of C 1-4 alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, and heterocyclic C 1-4 alkyl;
  • m is an integer having a value of 0 to 4.
  • m′ is 0, or an integer having a value of 1 or 2;
  • q is 0, or an integer having a value of 1 to 10;
  • s is an integer having a value of 1 to 3;
  • t is 0, or an integer having a value of 1 or 2.
  • Preferred compounds of the present invention are of the formula (II):
  • R b is independently selected from the group consisting of hydrogen, NR 6 R 7 , OH, OR a , C 1-5 alkyl, aryl, arylC 1-4 alkyl, aryl C 2-4 alkenyl, cycloalkyl, cycloalkyl C 1-5 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heteroarylC 2-4 alkenyl, heterocyclic, heterocyclic C 1-4 alkyl, and a heterocyclic C 2-4 alkenyl moiety, all of which moieties may be optionally substituted one to three times independently by a substituent selected from the group consisting of halogen, nitro, halosubstituted C 1-4 alkyl, C 1-4 alkyl, amino, mono or di-C 1-4 alkyl substituted amine, OR a , C(O)R a , NR a C(O)OR a , OC(O)NR 6 R 7 , hydroxy
  • R a is selected from a group consisting of alkyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, COOR a , and a heterocyclic C 1-4 alkyl moiety, all of which moieties may be optionally substituted;
  • m is an integer having a value of 0 to 3;
  • m′ is 0, or an integer having a value of 1 or 2;
  • n is an integer having a value of 0 to 5;
  • q is 0, or an integer having a value of 1 to 10;
  • t is 0, or an integer having a value of 1 or 2;
  • s is an integer having a value of 1 to 3;
  • R 1 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano,C 1-10 alkyl, halosubstituted C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkoxy, halosubstituted C 1-10 alkoxy, azide, S(O) t R 4 , (CR 8 R 8 ) q S(O) t R 4 , hydroxy, hydroxy substituted C 1-4 alkyl, aryl, aryl C 1-4 alkyl, aryl C 2-10 alkenyl, aryloxy, aryl C 1-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C 2-10 alkenyl, heteroaryl C 1-4 alkyloxy, heterocyclic, heterocyclic C 1-4 alkyl, heterocyclicC 1-4 alkyloxy, heterocyclicC 2-10 alkenyl, (CR 8 R 8 ) q NR 4 R 5 , (CR 8
  • R 4 and R 5 are independently selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl, heterocyclic, and heterocyclicC 1-4 alkyl; or R 4 and R 5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from oxygen, nitrogen and sulfur;
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, C 1-4 alkyl, heteroaryl, aryl, aklyl aryl, and alkyl C 1-4 heteroalkyl; or R 6 and R 7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom is selected from oxygen, nitrogen or sulfur, and which ring may be optionally substituted;
  • Y is selected from the group consisting of hydrogen, halogen, nitro, cyano, halosubstituted C 1-10 alkyl, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkoxy, halosubstituted C 1-10 alkoxy, azide, (CR 8 R 8 ) q S(O) t R a , (CR 8 R 8 ) q OR a , hydroxy, hydroxy substituted C 1-4 alkyl, aryl, aryl C 1-4 alkyl, aryloxy, arylC 1-4 alkyloxy, aryl C 2-10 alkenyl, heteroaryl, heteroarylalkyl, heteroaryl C 1-4 alkyloxy, heteroaryl C 2-10 alkenyl, heterocyclic, heterocyclic C 1-4 alkyl, heterocyclicC 2-10 alkenyl, CR 8 R 8 ) q NR 4 R 5 , C 2-10 alkenyl C(O
  • R 8 is hydrogen or C 1-4 alkyl
  • R 9 is hydrogen or a C 1-4 alkyl
  • R 10 is C 1-10 alkyl C(O) 2 R 8;
  • R 11 is selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4 alkyl, optionally substituted heterocyclic, and optionally substituted heterocyclicC 1-4 alkyl;
  • R 13 is selected from the group consisting of C 1-4 alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclic, or heterocyclicC 1-4 alkyl;
  • Illustrative compounds of Formula (I) and (II) include, but are not limited to:
  • Preferred compounds in the present invention have a half life of 2 hours or above, more preferably 5 hours or above, even more preferably 10 hours or above.
  • Preferred compounds of the present invention exhibit a clearance value Cl int of one or below, more preferably 0.8 or below, even more preferably 0.6 or below.
  • Preferred compounds of the present invention maintain the acidity of the phenol moiety, exhibiting a pKa of 8.5 or below, more preferably a pKa of 8.0 or below, even more preferably 7.0 or below.
  • the present invention discloses that the introduction of a sulfonamide or sulfoxide group ortho to the phenol reduced the rate of conjugation of the phenol and hence increased the half-life of the compounds in vivo.
  • Other functional groups were less effective in blocking glucuronidation of the phenol.
  • a series of IL-8 inhibitors containing a sulfonamide or sulfone ortho to the phenol were found to have reduced clearance when incubated with UDPGA (Uridinium diphosphate glucuronic acid) in liver microsomes as compared to the corresponding amides, sulfoxides, and alkyl substituted compounds (see Tables 1 and 2).
  • Three male Sprague-Dawley rats received surgically implanted catheters in the vena cava (via the femoral vein), and in the femoral artery at least three days prior to the study.
  • the animals (fed) received the compound as a 60 min iv infusion (4.0 mL/kg).
  • the animals (fasted) received the compound by oral gavage (16.0 mL/kg).
  • the pK a of a compound was measured using the following method.
  • the compound (20uM in a 10% DMSO solution) was added to a phosphate buffer solution.
  • the concentrations of compound were then measured using a UV (280 nm) plate reader. Linear regression analysis was then used to determine the pK a value as measured by the following equation:
  • pH pK a +log(( A max ⁇ A )/( A ⁇ A min ))
  • a max is the maximum of abs
  • a min is the minimum of abs.
  • the desired compounds of formula (I) can be obtained from commercially available sulfonic acids 1 as outlined in scheme 1.
  • the sulfonic acid 1 can be converted to the sulfuryl chloride 2 using methods well known in the art such as phosphorous oxychloride in refluxing toluene.
  • the sulfuryl chloride 2 can be coupled with the desired amine (HN(R b ) 2 ) to give the sulfonamide (I) using standard techniques well known in the art such as the desired amine in a suitable organic solvent such as methylene chloride in the presence of an amine base such as triethylamine.
  • the desired sulfonic acid 1 is not commercially available, it can be prepared from a commercially available thiol as outlined in scheme 2.
  • the sulfonic acid 2 can be prepared from the thiol 1 using oxidizing conditions well know in the art such as meta-chlorobenzoic acid (mCPBA) or sodium periodate (NaIO 4 ) in a suitable organic solvent such as methylene chloride.
  • mCPBA meta-chlorobenzoic acid
  • NaIO 4 sodium periodate
  • the desired substituted phenol sulfonamide (I) can be prepared by other methods.
  • the thiol precusor to phenol sulfonamide (I) can be abstained by a nucelophilic displacement reaction as outlined in scheme 3 (Zh. Organ. XIMII 1978, 14, 120(1), 187-192 and J. Med. Chem. 1989, 32, 2396).
  • the desired thiol 2 in scheme 3 can be obtained from a commercially available ortho chloro phenol 1 or ortho amino phenol 3 as outlined in scheme 3.
  • the ortho chloro phenol can be reacted with hydrogen sulfide or dichlorosulfide in the presence of zinc and hydrochloric acid to give the desired thiol 2.
  • the ortho amino phenol 3 can be converted to the thiol 2 via the intermediate azide (not shown).
  • the azide can be obtained from the aniline 3 using conditions well known in the art such as sodium nitrate (NaNO 3 ) in a suitable organic solvent such as methylene chloride.
  • the azide can be converted to the thiol 2 using potassium xanthate in a suitable organic solvent such as methylene chloride.
  • Scheme 4 oultines another method for preparing the desired thiol 2 starting from a commercially available substituted phenol 1 using nucleophilic aromatic substitution chemistry (J. Heterocyclic Chem. 1981, 18(6), 1161-1164).
  • the thiol group can be introduced by reacting a phenol 1 with the desired thiol (RSH) in the presence of silver oxide (Ag 2 O) in a suitable organic solvent such as methylene chloride.
  • the desired sulfonic acid 2 can also be obtained from a commercially available phenol 1 via electrophilic aromatic substitution chemistry as outlined in scheme 5 (Acta. Chem. Scand. 1979, B33(4), 261-264 and J. Med. Chem. 1981, 24(9), 1063-1067).
  • the phenol 1 can be reacted with either chloro sulfonic acid, sulfuric acid or sulfur trioxide under standard reaction conditions well known in the art to give the sulfonic acid phenol 2.
  • the desired phenolaniline 5 is not commercially available, it can be prepared as outlined in Scheme 2.
  • Commercially available 3-chloroaniline 1 can be converted to the amide 2 using standard conditions well known in the art such as pivotally chloride and triethylamine in a suitable organic solvent such as methylene chloride.
  • the amide 2 can be converted to the benzoxazole 3 using an excess amount of a strong base such as butyllithium in a suitable organic solvent such as THF under reduced reaction temperatures between ⁇ 20 and ⁇ 40° C. followed by quenching the reaction with sulfur trioxide gas.
  • the sulfonic acid 3 can be converted to the sulfonamide 4 using standard conditions well known in the art such as oxalylchloride in a suitable organic solvent such as methylene chloride to give the intermediate sunfonyl chloride.
  • the sulfonyl chloride intermediate can be transformed to the sulfonamide 4 using standard conditions well known in the art by reacting it with the amine HN(R b ) 2 in the presence of a suitable amine base such as triethylamine in a suitable organic solvent such as methylene chloride.
  • the desired phenolaniline 5 can be obtained from the benzoxazole 4 using standard hydrolysis conditions well known in the art such as sulfuric acid in water and heating at 90° C.
  • the desired diphenyl ureas 2 can be obtained by condnesing the aniline 1 with the desired isocyanate in a suitable organic solvent such as dimethylformamide (DMF) as outlined in scheme 7. If the desired isocyanate is not commercially available, the isocyanate can be prepared in situ from the aniline using conditions well known in the art such as triphosgene and triethylamine in a suitable organic solvent such as methylene chloride.
  • a suitable organic solvent such as dimethylformamide (DMF) as outlined in scheme 7.
  • the desired compounds of structure 6 can be prepared as outlined in Scheme 8.
  • Dichlorosquarate 2 can be prepared from squaric acid 1 using standard chlorination methods well known in the art such as oxalyl chloride and catalytic amounts of DMF in methylene chloride and heating at 45° C. Reacting dichlorosquarate 2 with the desired phenolaniline 3 in an organic solvent such as THF gives the mono-chlorosquarate 4. Reacting mono-chlorosquarate 4 with the desired aniline 5 in an organic solvent such as DMSO at room temperature or heating at 45° C. gives the target compound of formula 6.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US10/473,105 2001-03-30 2002-03-27 Methods of synthesizing phenol-contining compounds Abandoned US20040110954A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US10/473,105 US20040110954A1 (en) 2001-03-30 2002-03-27 Methods of synthesizing phenol-contining compounds

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US28041101P 2001-03-30 2001-03-30
PCT/US2002/010038 WO2002079122A2 (en) 2001-03-30 2002-03-27 Methods of synthesizing phenol-containing compounds
US10/473,105 US20040110954A1 (en) 2001-03-30 2002-03-27 Methods of synthesizing phenol-contining compounds

Publications (1)

Publication Number Publication Date
US20040110954A1 true US20040110954A1 (en) 2004-06-10

Family

ID=23072962

Family Applications (1)

Application Number Title Priority Date Filing Date
US10/473,105 Abandoned US20040110954A1 (en) 2001-03-30 2002-03-27 Methods of synthesizing phenol-contining compounds

Country Status (16)

Country Link
US (1) US20040110954A1 (cs)
EP (1) EP1383488A2 (cs)
JP (1) JP2005507366A (cs)
KR (1) KR20030088044A (cs)
CN (1) CN1529591A (cs)
AR (1) AR034299A1 (cs)
BR (1) BR0208510A (cs)
CA (1) CA2442480A1 (cs)
CZ (1) CZ20032639A3 (cs)
HU (1) HUP0500644A3 (cs)
IL (1) IL158014A0 (cs)
MX (1) MXPA03008946A (cs)
NO (1) NO20034288L (cs)
PL (1) PL373510A1 (cs)
WO (1) WO2002079122A2 (cs)
ZA (1) ZA200307443B (cs)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070249625A1 (en) * 2004-10-20 2007-10-25 Jakob Busch-Petersen Il-8 Receptor Antagonists
US20070249672A1 (en) * 2006-04-21 2007-10-25 Jakob Busch-Petersen IL-8 Receptor Antagonists
US20090093492A1 (en) * 2002-10-29 2009-04-09 Smithkline Beecham Corporation Il-8 receptor antagonists
US20090170871A1 (en) * 2006-06-23 2009-07-02 Smithkline Beecham Corporation IL-8 Receptor Antagonists
US20090298810A1 (en) * 2006-04-21 2009-12-03 Smithkline Beecham Corporation IL-8 Receptor Antagonists

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE60220778T2 (de) * 2001-04-16 2008-03-06 Schering Corp. 3,4-disubstituierte cyclobuten-1,2-dione als cxc-chemokinrezeptorliganden
UA103198C2 (en) 2008-08-04 2013-09-25 Новартис Аг Squaramide derivatives as cxcr2 antagonists
CA2783696A1 (en) 2009-12-17 2011-06-23 Galderma Research & Development Use of compounds in the treatment or prevention of skin disorders
SI2760821T1 (en) 2011-09-02 2018-02-28 Novartis Ag A salt salt of an anti-inflammatory substituted cyclobutenedione compound
KR20200037857A (ko) 2017-08-14 2020-04-09 알러간, 인코포레이티드 3,4-이치환된 3-시클로부텐-1,2-디온 및 그의 용도

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3691185A (en) * 1970-04-20 1972-09-12 Lewis H Sarett 5-aryl and arylphenyl sulfonic acids in treating inflammation
US3714232A (en) * 1969-06-25 1973-01-30 Merck & Co Inc 5-arylphenyl sulfonic acids
US4607030A (en) * 1982-03-06 1986-08-19 Hoechst Aktiengesellschaft 2-aminomethyl-6-sulfamoylphenol derivatives, a process for their preparation and their use and also pharmaceutical formulations based on these compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY25842A1 (es) * 1998-12-16 2001-04-30 Smithkline Beecham Corp Antagonistas de receptores de il-8

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3714232A (en) * 1969-06-25 1973-01-30 Merck & Co Inc 5-arylphenyl sulfonic acids
US3691185A (en) * 1970-04-20 1972-09-12 Lewis H Sarett 5-aryl and arylphenyl sulfonic acids in treating inflammation
US4607030A (en) * 1982-03-06 1986-08-19 Hoechst Aktiengesellschaft 2-aminomethyl-6-sulfamoylphenol derivatives, a process for their preparation and their use and also pharmaceutical formulations based on these compounds

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090093492A1 (en) * 2002-10-29 2009-04-09 Smithkline Beecham Corporation Il-8 receptor antagonists
US7709485B2 (en) 2002-10-29 2010-05-04 Glaxosmithkline Llc IL-8 receptor antagonists
US20070249625A1 (en) * 2004-10-20 2007-10-25 Jakob Busch-Petersen Il-8 Receptor Antagonists
US20070249672A1 (en) * 2006-04-21 2007-10-25 Jakob Busch-Petersen IL-8 Receptor Antagonists
US20090093451A1 (en) * 2006-04-21 2009-04-09 Smithkline Beecham Corporation IL-8 Receptor Antagonists
US20090298810A1 (en) * 2006-04-21 2009-12-03 Smithkline Beecham Corporation IL-8 Receptor Antagonists
US7893089B2 (en) 2006-04-21 2011-02-22 GlaxoSmithKline, LLC IL-8 receptor antagonists
US20110105563A1 (en) * 2006-04-21 2011-05-05 Jakob Busch-Petersen Il-8 receptor antagonists
US8097626B2 (en) 2006-04-21 2012-01-17 Glaxosmithkline Llc IL-8 receptor antagonists
US20090170871A1 (en) * 2006-06-23 2009-07-02 Smithkline Beecham Corporation IL-8 Receptor Antagonists
US20090281110A1 (en) * 2006-06-23 2009-11-12 Jakob Busch-Petersen Method of Treatment

Also Published As

Publication number Publication date
AR034299A1 (es) 2004-02-18
CA2442480A1 (en) 2002-10-10
HUP0500644A3 (en) 2005-11-28
MXPA03008946A (es) 2004-05-21
BR0208510A (pt) 2005-04-19
CN1529591A (zh) 2004-09-15
NO20034288L (no) 2003-12-01
EP1383488A2 (en) 2004-01-28
WO2002079122A3 (en) 2002-11-28
KR20030088044A (ko) 2003-11-15
HUP0500644A2 (hu) 2005-09-28
NO20034288D0 (no) 2003-09-25
PL373510A1 (en) 2005-09-05
JP2005507366A (ja) 2005-03-17
WO2002079122A2 (en) 2002-10-10
IL158014A0 (en) 2004-03-28
CZ20032639A3 (cs) 2004-04-14
ZA200307443B (en) 2004-10-29

Similar Documents

Publication Publication Date Title
ES2252996T3 (es) Derivados de bencenosulfonamida y su uso como inhibidores de mek.
ES2396715T3 (es) Derivados de ácido fenoxifenilacético 4-sustituido
US20070197627A1 (en) Indoline compound and process for producting the same
US20040110954A1 (en) Methods of synthesizing phenol-contining compounds
PL95987B1 (pl) Sposob wytwarzania pochodnych 2-karba-minianobenzimidazolu podstawionych w pozycji 5 lub 6 pierscienia benzenowego
JPH05140080A (ja) フエニルスルホンアミド誘導体
HUP0104122A2 (hu) N-Aril-szulfonil-aminosav-omega-amidok, eljárás a vegyületek előállítására és ezeket tartalmazó gyógyászati készítmények
JPS62238236A (ja) アルコキシサリチル酸誘導体の製造方法
AU2002256009A1 (en) Methods of synthesizing phenol-containing compounds
US4504490A (en) Substituted benzenesulfonic esters and their use as medicaments for combatting helminths
US20090012307A1 (en) Process for the Preparation of 4-(imidazol-1-yl)benzenesulfonamide Derivatives
HUT53878A (en) Process for producing substituted (quinoline-2-il-methoxy)-phenyl-n,n'-sulfonyl-carbamides and pharmaceutical preparations containing the compounds
IL127783A (en) 4 - iodo -2[n - (n - alkylaminocarbonyl) - aminosulfonyl] benzoic acid methyl ester and derivatives thereof and method for their production
Tomé et al. Chlorosulfonation of N-arylmaleimides
KR100459938B1 (ko) 농·의약 합성중간체로 유용한 불소 치환기 함유헤테로고리 화합물 및 이의 제조방법
JP2025030753A (ja) 炭酸脱水酵素用標的共有結合性阻害剤
RU2128164C1 (ru) Производные n-карбониланилинов и способ их получения
JP2533690B2 (ja) スルホンアミド誘導体
JPH051023A (ja) アルカンスルホンアニリド誘導体の製法
CN118146163A (zh) 一种苯并咪唑衍生物及其制备方法
JPH11140064A (ja) １，２，３−チアジアゾール誘導体の製造方法及び中間体化合物
JPH0641088A (ja) スルホニル尿素の製造方法
CN1100754C (zh) 三氟乙酰乙酰苯胺的制备方法
AU665129B2 (en) Manufacturing of pesticides and intermediates
ZA200207326B (en) IL-8 receptor antagonists.

Legal Events

Date Code Title Description
AS Assignment

Owner name: SMITHKLINE BEECHAM CORPORATION, PENNSYLVANIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PALOVICH, MICHAEL R.;WIDDOWSON, KATHERINE L.;REEL/FRAME:014965/0245;SIGNING DATES FROM 20030424 TO 20030426

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION